4-(substituted anilino)-2-phenyl-5-pyrimidinecarboxylic acid esters

ABSTRACT

1. A COMPOUND HAVING THE FORMULA   2-(PHENYL-),4-(R5-(R6-1,2-PHENYLENE)-N(-R4)-),5-(R3-OOC-)-   PYRIMIDINE   WHERE R3 IS HYDROGEN OR LOWER ALKYL; R4 IS HYDROGEN OR LOWER ALKYL; R5 IS HYDROXY, LOWER ALKOXY, OR LOWER ALKANOYL; AND R6 IS HYDROGEN, HALOGEN, OR NITRO.

United States Patent Office 3,850,931 Patented Nov. 26, 1974 US. Cl. 260-256.4 N 8 Claims ABSTRACT OF THE DISCLOSURE The disclosure is directed to the method of preparing and the resultant products of pyrimido [5,4-c] [1,51-benzoxazepin-5(llg)-ones and inter-mediates having the general formulae:

I Toma flown N NR 32 I a a e (I) 0 t o W Rs (III) This application is a division of our application 156,941 filed June 25, 1971, now US. Pat. No. 3,759,922.

This invention relates generally to the preparation of pyrimidobenzoxazepinones and to intermediates in their preparation. The invention is particularly directed to c0mpounds having the structural formulae:

meow 002R3 1 l l I /\0 /\NR I 5 where R is hydrogen or lower alkyl; R is hydrogen, nitro, amino, or lower alkylamino; R is hydrogen or lower alkyl; R is hydrogen or lower alkyl; R is hydroxy, lower alkoxy, or lower alkanoyl; R is hydrogen, halogen, or nitro; R is lower alkyl or lower alkanoyl; and R is hydrogen, halogen or nitro.

As defined herein, the terms lower alkyl, lower alkoxy, lower alkanoyl," and the like, describe groups having from one to four carbon atoms in a straight-or branched chain.

A typical example of the compounds of this invention which are depicted by structural formula (I) is 4-(0-nitrophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester.

A typical example of the compounds of this invention which are depicted by structural formula (II) is 4-(0- hydroxyanilino)-2-phenyl-S-pyrimidinecarboxylic acid.

A typical example of the compounds of this invention which are depicted by structural formula (III) is N-ethyl- Z-phenylpyrimido [5,4-c] 1,5 benzoxazepine-S 1 lgyone.

The new and useful compounds of this invention may be prepared by the process which is hereinafter schematically illustrated, R R being defined as described above:

REACTION SCHEME I REACTION SCHEME I I mm .1. ,An alternate method for the preparation of the new and useful products of this invention is hereinafter schematican' illustrated, R R being defined as described above.

REACTION SCHEME II (xIv) (xv) u a C0271 I 002R]. c u kN/[NRIO G. c H

5 .OH 6 5 o xvII (XVI).

(xvrn) Where R is lower alkanoyl, and R is lower alkyl.

When R is ethyl and R is n-propyl, an alternative r synthetic scheme, Reaction Scheme III, as outlined hereinafter was employed, R --R being defined as described above.

REACTION SCHEME III R is hydrogen or lower alkyl R is lower alkyl The starting materials used in the preparation of the compounds of this invention are generally known and can be prepared by well-known procedures.

As is shown in Reaction Scheme I the intermediate products of the invention may be prepared by a number of methods.

Method 1: In a first method 5-carbethoxy-4-chloro-2- phenylpyrimidine (IV) is reacted with o-nitrophenol affording 4-(o-nitrophenoxy) -2-pheny1-S-pyrimidinecarboxylic acid, ethyl ester (V) which may be catalytically reduced to alford 4-(o-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester (VI).

Method 2: In an alternate method 5-carbethoxy-4- chloro-Z-phenylpyrimidine (IV) may be refluxed with oaminophenol to directly afford 4-(o-hyd'roxyanilino)-2- phenyl-5-pyrimidinecarboxylic acid, ethyl ester (VI). It has been found that in carrying out the latter method, there is produced in intermediate 4-(2-arninophenoxy)-2- phenyl-5 -pyrimidinecarboxylic acid, ethyl ester (VII) which readily rearranges to afiord 4-(0-hydroxyanilino)- 2-phenyl-S-pyrimidinecarboxylic acid, ethyl ester (VI).

Referring to Reaction Scheme 1, refluxing for 1 to 5 hours, a mixture of 4-(0-hydroxyanilino) 2 phenyl-5- pyrimidinecarboxylic acid, ethyl ester (VI), 40 percent aqueous potassium hydroxide and ethanol, followed by chilling of the reaction mixture, filtration, dissolving the precipitate in hot water, and acidification affords the product 4-(o-hydroxyanilino) 2 phenyl 5 pyrimidinecarboxylic acid (VIII).

As an alternative, 4-(o-hydroxyanilino(-2-phenyl-5- pyrimidinecarboxylic acid (VIII) may be prepared by refluxing a mixture of 4-(2-aminophenoxy) 2 phenyl-5- pyrimidinecarboxylic acid, ethyl ester (VII), 15 percent aqueous sodium hydroxide solution and ethanol for about 1 to 3 hours. Acidification of the reaction mixture, for instance with hydrochloric acid, to about pH 2 affords the product as a precipitate which may be collected and purified, for instance by filtration and washing with water.

A mixture of 4-(o-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid (VIII) and acetic anhydride is heated to reflux temperatures and a clear solution is obtained in 5 to 30 minutes. Reflnxing is continued for 15 to 75 minutes then the excess acetic anhydride is removed under reduced pressure. On chilling, the residue solidifies to afiord the product ll-acetyl 2 phenylpyrimido[5,4-c] [1,5 ]-benzoxazepin-5 1 15) -one (IX).

To a pyridine solution containing 4-(2-aminophenoxy)- Z-phenyl-S-pyrimidinecarboxylic acid, ethyl ester (VII) is added drop-wise acetic anhydride under chilling. Chilling and stirring are continued for /2 to 2 hours until a pre cipitate deposits. The precipitate is collected by filtration and Washed with water to afford the product 4-(2-N-acetylaminophenoxy) 2 phenyl 5 pyrimidinecarboxylic acid, ethyl ester (X).

A mixture of 11-acetyl-2-phenylpyrimido[5,4-c][1,5]- benzoxazepin 5 (11E) one (IX), absolute ethanol and concentrated hydrochloric acid is stirred at room temperature for 10 to 30 minutes and chilled in an ice bucket. The precipitate is collected on a filter and washed with ethanol, then with water, and the product recrystallized from dimethylformamide, affording the product 4-(o-hydroxyanilino)-2phenyl-5-pyrimidinecarboxylic acid, acetate (XII).

To a pyrimidine solution of 4-(5-chloro-2-hydroxyanilino)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester (VI) is added drop-wise acetic anhydride and the resultant mixture refluxed for 15 minutes to 1 hour. Chilling of the reaction mixture causes separation of the precipitate which is collected on a filter and washed with ethanol to afford the product. Recrystallization from pyridine purifies the product 4 (3-chloro-6-hydroxyanilino)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester, acetate (XI).

A mixture of 4-(Z-N-acetylaminophenoxy) 2 phenyl- S-pyrimidinecarboxylic acid, ethyl ester (X) and pyridine is refluxed for 1 to 4 hours and then the excess pyridine is removed under reduced pressure to yield an oil which crystallizes on chilling. The product is 4-(3- chloro-6-hydroxyanilino)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester, acetate (XI).

The pyrimido [5,4 c] [1,5]benzoxazepin 5 (11g)- ones, in which R is ethyl, n-propyl or n-butyl, may be prepared as shown in Reaction Scheme II. To a pyridine solution containing o-aminophenol (XIII) is added slowly acetic anhydride whereby an exothermic reaction takes place. When the reaction has subsided, the reaction mix ture is heated on a steam bath for to 60 minutes, then chilled in a freezer. The precipitate thus separated is collected on a filter and washed with water to yield the product o-N-acetylaminophenol, acetate (XIV). The product o-N-acetylaminophenol, acetate (XIV) is dissolved in tetrahydrofuran and is added drop-Wise to a suspension of lithium aluminum hydride in tetrahydrofuran. The resulting mixture is stirred at room temperature for /z to 4 hours, then contacted with water, percent sodium hydroxide, and water successively. After removing the inorganic salt by filtration, the tetrahydrofuran is evaporated under reduced pressure. Acidification of the residue, for instance with the 3 normal hydrochloric acid, causes separation of a precipitate which is collected on a filter under a nitrogen atmosphere as the product Z-N-ethylaminophenol (XV). To the product Z-N-ethylaminophenol (XV) in ethanolic solution is added in small portions 5 carbethoxy 4 chloro 2 phenylpyrimidine (IV) with Warming on a steam bath. The resulting mixture is refluxed for 15 to 90 minutes. Addition of a large amount of water causes separation of a precipitate which is collected, for instance on a filter, and washed with water, then with ether, to yield the product 4*(0- ethylaminophenoxy) 2 phenyl 5 pyrimidinecarboxylic acid, ethyl ester (XVI).

A mixture of 4 (o ethylaminophenoxy) 2 phenyl- S-pyrimidinecarboxylic acid, ethyl ester (XVI), 15 percent aqueous sodium hydroxide solution and ethanol is refluxed for /2 to 3 hours then acidified, for instance with dilute hydrochloric acid, to a pH of about 2. The precipitate thus deposited is collected on a filter and washed with ethanol then with water to yield a product which is 4 (N ethyl 0 hydroxyanilino) 2 phenyl 5 pyrimidinecarboxylic acid (XVII). The product may be puritfied by recrystallization from ethanol or water if desired.

A mixture of 4 (N ethyl 0 hydroxyanilino)-2 phenyl-S-pyrimidinecarboxylic acid (XVII) and acetic anhydride is refluxed for 1 to 5 hours. Removal of the excess acetic anhydride under reduced pressure affords an oil which solidifies on standing to yield the product 11 ethyl 2 phenylpyrimido [5,4- c][1,5]benzoxazepin-5-(1l I:I )-one (XVIII) which may be purified by recrystallization from absolute ethanol.

Compounds of structure XIX were prepared, as shown in the reaction scheme III, by heating a mixture of 4-chl0ro-2-phenyl-S-pyrimidinecarboxylic acid, ethyl ester, sodium carbonate, an appropriate aniline, and ethanol (reaction solvent) under reflux for 1 to 2 hrs., then working up the reaction mixture by a standard procedure.

In the pharmacological evaluation of the biological activity of the compounds of this invention, the in vivo effects are tested as follows. The compound is administered intraperitoneally to three mice (14 to 24 grams) at each of the following doses: 400, 127, 40 and 12.7 mg./kg. The animals are Watched for a minimum of two hours during which time signs of general stimulation, (i.e., increased spontaneous motor activity hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration) autonomic activity (i.e., miosis, mydriasis, diarrhea) are noted.

When evaluated in the foregoing pharmacological procedure the compounds of this invention produced decreased motor activity and decrease respiration at a dose 6 of 12.7 to 400 MPK, which is proof of central nervous system depressant activity. While some compounds showed no CNS depressant activity at the maximum dose tested, it is believed that all would show such activity at higher dose ranges. None of the compounds were toxic at the highest dose tested.

When the compounds of this invention are employed as described above, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportions of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain types of clay and so forth. They may be administered sublingally in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, flavoring agents and dyes; and then dehydrated sufliciently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, the treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the present invention, specific examples of the practice of the invention are hereinafter given. It should be understood, however, that this is done solely by way of example and is intended neither to delineate the scope of the invention nor limit the ambit of the appended claims.

For brevity the following abbreviations are used in the examples: g. for gram or grams, ml. for milliliter or milliliters, hr. for hour or hours, for degrees centigrade, mp for melting point, 0" for phenyl orC H dec. for decomposed, and MPK for milligrams per kilogram of host body weight.

EXAMPLE 1 The following exemplifies the preparation of 4-(0- nitrophenoxy) 2 phenyl 5 pyrimidinecarboxylic acid, ethyl ester, a compound of structure V.

o-Nitrophenol (14 g.) was added to a sodium methoxide-methanol solution obtained by dissolving 2.3 g. of sodium in ml. of absolute methanol whereby a dark red color developed. After removing the methanol under reduced pressure, 70 ml. of dimethylformamide and 26.3 g. of 4 chloro 5 carbethoxy 2 phenylpyrimidine were added, and the mixture was refluxed for 1 hr. The hot reaction mixture was filtered and the filtrated was chilled in ice to cause precipitation of product. The product weighed 29 g. and melted at -154". Recrystallization of the product from absolute ethanol afforded an analytical sample, mp 151-154".

Based on the assumed molecular formula C H N O it was calculated that the elemental analysis by weight would be 62.46 percent carbon, 4.14 percent hydrogen and 11.50 percent nitrogen. The product was analyzed and found to contain 62.33 percent carbon, 4.09 percent hydrogen, and 11.36 percent nitrogen which confirmed the accuracy of the assumed formula. This may be expressed.

Anal.

Calcd. for C19H115N3O2: C, H, N, Found: C, 62.33; H, 4.09; N, 11.36.

When evaluated in the foregoing pharmacological procedure the latter compound was found to be a mydriatic agent at a dose of 400 M-PK.

Following the procedure of Example 1, but substituting appropriate starting materials, products having the following substituents may be prepared.

EXAMPLE 2 The following exemplifies the preparation of 4-(0-hydroxyanilino)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester, a compound of structure VI.

A mixture obtained by dissolving 2.0 g. of 4-(o-nitrophenoxy)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester (V) and 0.5 g. of Palladium Charcoal in 200 ml. of absolute ethanol was reduced catalytically at 50 over a period of 75 min. After removing the catalyst by filtration, the ethanolic solution was concentrated to about 60 ml., and chilled in an ice-bucket. The product was collected by filtration, then recrystallized from absolute ethanol, mp 178.5-181, yield 1.8 g.

Anal.

Calcd. for C I-1 N 0 C, 68.05; H, 5.11; N, 12.53. Found: C, 68.33; H, 4.81; N, 12.70.

Following the procedure of Example 2, but substituting appropriate starting materials, products having the following substitutents may be prepared.

l w C0115- HO (v1) 8 EXAMPLE 3 The following exemplifies the preparation of 4-(0-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester, a compound of structure VI.

I. o-Aminophenol (3.3 g.) was added to 50 ml. of absolute methanol containing 0.7 g. of sodium, then the methanol was removed in vacuo to give sodium salt .of the 0- aminophenol. Dimehtylformarnide was added to the reaction flask. To this solutoin was added 5-carbethoxy-4- chloro-2-phenylpyrimidine (7.9 g.). An exothermic reaction takes place. The reaction mixture was stirred at room temperature for 0.5 hr., then poured into a large amount of ice water which caused separation of the product, mp 178-181 II. In an alternate method of preparation, to a mixture containing 2.2 g. of o-aminophenol and 0.46 g. of sodium in 45 ml. of ethanol was added 5-carbethoxy-4-chloro-2- phenylpyrimidine. The resulting mixture was refluxed for 1 hr. Chilling of the reaction mixture caused separation of product which was collected on a filter, mp -173"; yield 4.5 g. Recrystallization from ethanol raised the mp to 178-181".

Following the procedure of Example 3, but substituting appropriate starting materials, products having the following substituents may be prepared.

/W-OOzRa I l NH Example 3- ggg ggmmmmmm EXAMPLE 4 The following exemplifies the preparation of 4-(5- chloro-2-hydroxyanilino) 2 phenyl 5-pyrimidinecarboxylic acid, ethyl ester, a compound of structure VI.

To a mixture containing 7.0 g. of 2-amino-4-chlorophenol and 1.2 of sodium in 300 ml. of absolute ethanol was added 13.0 g. of 5-carbethoxy-4-chloro-2-pheny1- pyrimidine. The resulting mixture was refluxed for 2 hr., then chilled. A precipitate was collected on a filter and washed with ethanol several times then with water to give 13.6 g. of product, mp 247-251 This compound is identical with the product obtained by Example 8.

When tested in the foregoing pharmacological evaluation, the latter compound caused decreased motor activity at a dose of 127 MPK administered orally and decreased respiration at a dose of 127 MPK administered orally.

Following the procedure of Example 4, but substituting appropriate starting materials, products having the following substituents may be prepared.

lggg-wggmtdmmmm C4HD EXAMPLE 5 The following exemplifies the preparation of 4-(2-hydroxy-S-nitroanilino)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester, a compound of structure VI.

I. 2-Amino-4-nitrophenol (7.5 g.) was added to 70 ml. of methanol containing 1.2 g. of sodium. Removal of the methanol from the resulting solution in vacuo afforded sodium salt of the 2-amino-4-nitrophenol which was then dissolved in 5.0 ml. of dimethylformamide. To the resulting solution was added 13.0 g. of 4-carbethoxy-4-chloro- Z-phenylpyrimidine, and stirred at room temperature for 0.5 hr. The reaction mixture was then warmed on a steam bath for min., then poured into a large amount of cold water. A precipitate thus deposited Was collected on a filter and washed with water several times. Recrystallization of the residue on the filter from dimethylformamide afiorded 10 g. of product, mp 277279 dec. Another recrystallization from dimethylformamide raised the mp to 285286 dec.

Anal.

Calcd. for C H N O C, 59.99; H, 4.24; N, 14.73. Found: C, 59.87; H, 4.32; N, 14.50.

H. This compound can also be prepared from the 5- carbethoxy 4 chloro 2 phenylpyrimidine and 2- amino-4-nitrophenol using ethanol as a reaction solvent as described in the preparation of 4-(5-chloro-2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester.

Following the procedure of Example 5, but substituting appropriate starting materials, products having the following substituents may be prepared.

10 EXAMPLE 6 The following exemplifies the preparation of 4 (2- aminophenoxy)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester, a compound of structure VII.

o-Aminophenol (3.3 g.) was added to 50 ml. of absolute methanol containing 0.7 g. of sodium. After stirring the resulting solution for a few min. the methanol was removed in vacuo to give sodium salt of the o-aminophenol. The salt was dissolved in ml. of dimethylformamide. To the resulting solution was added in small portions 7.9 g. of 5-carbethoxy-4-chloro Z-phenylpyrimidine under cooling in ice. The cooling and stirring was continued for 15 more min. Pouring of the reaction mixture into a large amount of cold water caused separation of an oil which solidified on scratching. The solid material was collected on a filter and a fractional recrystallization from ether under dry ice-isopropanol chilling separated into two fractions. Another recrystallization of the more soluble fraction from ether afforded the product which melted at 102 solidified then remelted at 173-175 Anal.

Calcd. for C H N O C, 68.05; H, 5.11; N, 12.53. Found: C, 68.05; H, 5.11; N, 12.24. Following the procedure of Example 6, but substituting appropriate starting materials, products having the following substituents may be prepared.

(VII) EXAMPLE 7 The following exemplifies the preparation of 4-(2- amino 4 chlorophenoxy) 2 phenyl-S-pyrimidinecarboxylic acid, ethyl ester, a compound of structure VII.

The title compound was prepared as in Example 6 from 2 amino 4-chlorophenol and 5-carbethoxy-4-chloro-2- phenylpyrimidine, and crude product was recrystallized from absolute ethanol, mp 144146 (solidified and remelted at 246-250).

Anal.

Calcd. for C H ClN O C, 61.71; H, 4.36; N, 11.36;

Cl, 9.59. Found: C, 61.78; H, 4.41; N, 11.34; Cl 9.45.

EXAMPLE 8 1 1 recrystallized from dimethylformamide to give 1.0 g. of product, mp 25 l253.

Anal.

Calcd. for C H C1N O C, 61.71; H, 4.36; N, 11.36;

Cl, 9.59. Found: C, 61.38; H, 4.49; N, 11.54; Cl, 9.30.

EXAMPLE 9 The following exemplifies the preparation of 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester, a compound of structure VI.

The title compound was prepared as in Example 8 from 4 (Z-aminophenoxy)-2-phenyl-S-pyrimidinecarboxylic acid, mp 178-181.

EXAMPLE 10 The following exemplifies the preparation of 4-(o-hydroxyanilino) 2-phenyl-S-pyrimidinecarboxylic acid, a compound of structure VIII.

A. A mixture of 4(o-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl-ester (VI) (3.2 g.), 40% aqueous potassium hydroxide (10 ml.) and ethanol (20 ml.) was refluxed for 2 /2 hr. Chilling the reaction mixture caused precipitation of the sodium salt of the product which was collected on a filter. The precipitate was dissolved in hot water, and acidified with 3 N hydrochloric acid which caused precipitation of a product. This prod uct was collected on a filter and washed with water. The washed material was dissolved in 0.5 N NaOH, filtered and the filtrate acidified with 1 N HCl to give 2.0 g. of product, mp 285-289" dec.

Anal.

Calcd. for C H N O C, 66.44; H, 4.26; N, 13.68. Found: C, 66.51; H, 4.15; N, 13.48.

B. A mixture of 4-(0-anilinophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester (VII) (0.3 g.), 15% aqueous NaOH solution ml.) and ethanol (3 ml.) was refluxed for 2 hr. Acidification of the reaction mixture with 3 N HCl to pH 2 caused separation of a precipitate which was collected on a filter and washed with water several times to give 0.28 g. of product, (VIII) mp 290-292" dec. A mixture mp with a sample prepared from 4- (o-hydroxyanilino -2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester was not depressed.

C. A mixture of 11 acetyl-2-phenylpyrimido[5,4-c] [l,5]benzoxazepin-5(l1E)-one (IX) (0.25 g.) and 10% aqueous NaOH solution (20 ml.) was refluxed for 2 hr., then acidified with 3 N HCl. A precipitate was collected on a filter and washed with water several times to give the product, mp 298 dec.

Following the procedure of Example 10, but substituting appropriate starting materials, products having the following substituents may be prepared.

00211 R CaH5%NJ Ht') Example 10- B Cl C Br

EXAMPLE 11 The following exemplifies the preparation of 4-(5-chloro 2 hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, a compound of structure VIII.

A mixture of 4-(5-chloro-2-hydroxyanilino)-2-pheny1- S-pyrimidinecarboxylic acid, ethyl ester (VI) (10.0 g.), 20% aqueous NaOH solution (200 ml.) and ethanol (10 ml.) was refluxed for 20 min., then acidified with dilute 12. HCl. A precipitate separated, was collected on a filter and washed with water several times, mp 295297 dec. Purification by base-acid treatment raised the mp to 298 300 dec.

Anal.

Calcd. for C H ClN O C, 59.76; H, 3.54; N, 12.30. Found: C, 59.59; H, 3.58; N, 12.44.

EXAMPLE 12 The following exemplifies the preparation of 4-(2-hydroxy 5 nitroanilino)-2-phenyl-5-pyrimidinecarboxylic acid, a compound of structure VIII.

4-(2 Hydroxy-S-nitroanilino)-2-phenyl-4-pyrimidinecarboxylic acid was prepared from 4-(2-hydroxy-5-nitroanilino)-2-phenyl-S-pyrimidinecarboxylic acid, ethyl ester (VI) by base hydrolysis as in the previous example, nip 330 dec.

Anal.

Calcd. for C H N O -H O: C, H, N,

15.13. Found: C, 55.24; H, 3.60; N, 14.88.

Following the procedure of Example 12, but substituting appropriate starting materials, products having the following substituents may be prepared.

The following exemplifies the preparation of ll-acetyl- 2 phenylpyrimido[5,4-c] [1,5 ]benzoxazepin-5( 1 111) one, a compound of structure IX.

A mixture of 1.0 g. of 4-(o-hydroxyanilino)-2-phenyl S-pyrimidinecarboxylic acid (VIII) and 25 m1. of acetic anhydride was heated to reflux. A clear solution was obtained in 15 min. Refluxing was continued for 45 min., then the excess acetic anhydride was removed under re duced pressure. The residue solidified on chilling to give 0.55 g. of product, mp 2l9-225. Recrystallization from acetic anhydride afforded an analytical sample, mp 221- 223.5.

Anal.

Calcd. for C19H13N3O3: C, H, N, Found: C, 69.08; H, 3.70; N, 12.61.

Following the procedure of Example 13, but substituting appropriate starting materials, products having the following substituents may be prepared.

N O H I R R (IX) Example 13 A Acetyl H B Propionyl..- H C Acetyl 01 D Butyrvl. F E Propionyl... I

13 EXAMPLE 14 The following exemplifies the preparation of ll-acetyl- 9-chloro 2 phenylpyrimido[5,4-c] [1,5]benzoxazepin-5 (l1H)-one, a compound of structure IX.

A mixture of 4-(2-hydr0xy-5-chloroanilino)-2-phenyl- S-pyrimidinecarboxylic acid (VIII) (4.5 g.) and acetic anhydride (100 ml.) was gently refluxed for 2.5 hr., treated with charcoal, and filtered. Chilling of the filtrate caused separation of a precipitate which was collected on a filter, and dried over KOH in vacuo at 100 to give 1.5 g. of product, mp 223-228. Recrystallization of the crude product from acetic anhydride raised the mp to 243-246.

Anal.

Calcd. for C19H12C1N303I C, H, N,

11.49. Found: C, 62.73; H, 3.20; N, 11.52.

When tested in the foregoing pharmacological evaluation, the latter compound caused decreased motor activity at a dose of 12.7 MPK administered parenterally and decreased respiration at a dose of 12.7 MPK administered parenterally.

EXAMPLE 15 The following exemplifies the preparation of ll-acetyl- 9nitro-2-phenylpyrimido[5,4-c]benzoxazepin 5(11.[ one, a compound of structure IX.

A mixture of 4-(2-hydroxy-5-nitroanilino)-2-phenyl-5- pyrimidinecarboxylic acid (VIII) (1.1 g.) and acetic anhydride (25 ml.) Was refluxed for 1.5 hr. Chilling of the reaction mixture caused separation of a precipitate which was collected on a filter. Repeated recrystallization from acetic anhydride afforded 0.7 g. of an analytical sample, mp 284-285.

Anal.

Calcd. for C H N O C, 60.64; H, 3.21; N, 14.89. Found: C, 60.49; H, 3.34; N, 15.06.

Following the procedure of Example 15, but substituting appropriate starting materials, products having the following substituents may be prepared.

N02 (IX) Example 15 A- Acetyl H B Propionyl.-- H C Acetyl 01 D Butyryl F E Propionyl..- I

EXAMPLE 16 The following exemplifies the preparation of 4-(2-N- acetylaminophenoxy) 2 phenyl-S-pyrimidinecarboxylic acid, ethyl ester, a compound of structure X.

To a pyridine solution containing 4-(0-aminophen0xy)- 2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester (VII) (2.0 g.) was added dropwise acetic anhydride (1.0 g.) under chilling. The chilling and stirring was continued for 1 hr., whereby a precipitate deposited. The precipitate was collected on a filter and washed with water to give 1.7 g. of product, mp 140. Recrystallization from absolute ethanol afforded an analytical sample, mp 138- 140.

Anal.

Calcd. for C H N O C, 66.83; H, 5.07; N, 11.14. Found: C, 66.45; H, 5.00; N, 11.20.

Following the procedure of Example 16, but substituting appropriate starting materials, products having the following substituents may be prepared.

The following exemplifies the preparation of 4-(0-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, acetate, a compound of structure XII.

A mixture of 11-acetyl-2-phenylpyrimido[5,4-c][1,5] benzoxapin-5(11g)-one (IX) (0.5 g.), absolute ethanol (17 ml.) and concentrated HCl (4 drops) was stirred at room temperature for 20 min., then chilled in an icebucket. A precipitate was collected on a filter and washed with ethanol then with water. The crude product was then recrystallized from dimethylformamide, mp 232- 234 dec.

Anal.

CalCd. for C1gH15N304: C, H, N, 12.03. Found: C, 64.93; H, 4.60; N, 12.28.

Following the procedure of Example 17, but substituting appropriate starting materials, products having the following substituents may be prepared.

(XII) Example 17- A Acetyl.

Propionyl. Butyryl. i-Propionyl. Acetyl.

EXAMPLE 18 The following exemplifies the preparation of 4-(o-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester, acetate, a compound of structure XI.

A. To a solution obtained by dissolving 1.0 g. of 4- (2 hydroxy-anilino)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester (VI) in 15 ml. of pyridine was added dropwise 0.4 g. of acetic anhydride. The resulting mixture was heated on a steam bath for 1 hr. The pyridine was removed under reduced pressure to give a crystalline residue. Recrystallization from cyclohexane afforded an analytical sample, mp 152-154; yield 0.5 g.

Anal.

Calcd. for C H N O C, 66.83; H, 5.07; N, 11.13. Found: C, 66.75; H, 5.32; N, 11.27.

B. A mixture of 4-(Z-N-acetylaminophenoxy)-2-phenyl5-pyrim1dinecarboxylic acid, ethyl ester (X) (0.7 g.)

EXAMPLE 19 The following exemplifies the preparation of 4-(3-chloro-6-hydroxyanilino)-2-phenyl pyrimidinecarboxylic acid, ethyl ester, acetate, a compound of structure XI.

A. To a pyridine solution containing 3.7 g. of 4-(5- chloro-Z-hydroxyanilino)-2-phenyl 5 pyrimidinecarboxylic acid, ethyl ester (VI) was added dropwise 2.0 g. of acetic anhydride. The resulting mixture was refluxed for /2 hr. Chilling of the reaction mixture caused separa tion of a precipitate which was collected on a filter and washed with ethanol to give 3.2 g. of product, mp 159 160. Recrystallization from pyridine raised the mp to Anal.

Calcd. for C H ClN O C, 61.10; H, 4.64; N,

10.18; Cl, 8.59. Found: C, 61.17; H, 4.74; N, 10.37; Cl, 8.84.

B. A mixture of 4-(3-chloro-6-hydroxyanilino)-2-phenyl-S-pyrimidinecarboxylic acid, acetate (XI) (0.3 g.) and ethyl chloroformate (20 ml.) was refluxed overnight. Removal of the excessethyl chloroformate under reduced pressure afforded a solid residue which was then recrystallized from aniline, mp 144145. Infrared spectrum of this compound is identical with that of 4-(3-chloro-6-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester, acetate (XI) prepared from 4-(5-chloro-2-hydroxyanilino)-2-phenyl-S-pyrimidinecarboxylic acid, ethyl ester (VI) and acetic anhydride.

Following the procedure of Examples 18 and 19, but substituting appropriate starting materials, products having the following substituents may be prepared.

WQJOBR l l The following exemplifies the preparation of o-N-acetylaminophenol, acetate, a compound of structure XIV.

To a pyridine solution (40 ml.) containing 9.6 g. of o-aminophenol (9.6 g.) was added slowly 19.8 g. of acetic anhydride whereby an exothermic reaction took place. When the reaction was subsided, the reaction mixture was heated on a steam bath for 0.5 hr., then chilled in a freezer. A precipitate thus separated was collected on a filter and washed with water to give 12.4 g. of product, m.p. 122-125.

Following the procedure of Example 20, but substituting the appropriate starting materials, products having the following substituents may be prepared.

(XIV) EXAMPLE 21 The following exemplifies the preparation of 2-N- ethylaminophenol, a compound of structure XV.

To a suspension of lithium aluminum hydride (2.48 g.) in 35 ml. of tetrahydrofuran was added dropwise o-N- acetylaminophenol, acetate (8.4 g.) dissolved in ml. of tetrahydrofuran. The resulting mixture was stirred for 2 hr. of tetrahdyrofuran. The resulting mixture was stirred for 2 hr., then treated with 2.5 ml. of water, 2.5 ml. of 15% NaOH, and 7.5 ml. of water successively. After removing inorganic salt by filtration, the tetrahydrofuran was evaporated under reduced pressure. Acidification of the residue with 3 N HCl caused separation of a precipitate which was collected on a filter under nitrogen atmosphere, and used directly in the following step.

Following the procedure of Example 21, but substituting appropriate starting materials, products having the following substituents may be prepared.

EXAMPLE 22 The following exemplifies the preparation of 4-(0-ethylaminophenoxy) 2 phenyl-5-pyrimidinecarboxylic acid, ethyl ester, a compound of structure XVI.

To an ethanolic solution containing -ethylaminophenol obtained from -N-acetylaminophenol, acetate (XIV) (44.5 g.) in 70 ml. of absolute ethanol was added in small portions 15 g. of 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester (IV) with Warming on a steam bath. The resulting mixture was refluxed for 45 min. Addition of a large amount of water caused separation of a precipitate which was collected on a filter and washed with water then with ether to give 23 g. of product, m.p. 167.

Anal.

Calcd. for C H N O C, 69.40; H, 5.83; N, 11.56. Found: C, 69.28; H, 5.94; N, 11.57.

When tested in the foregoing pharmacological evaluation, the latter compound caused decreased motor activity at a dose of 127 MPK administered parenterally and decreased respiration at a dose of 127 MPK administered parenterally.

17 Following the procedure of Example 22 but substituting appropriate starting materials, products having the fole lowing substituents may be prepared.- j

EXAMPLE 23 The following exemplifies the preparation of 4-(N-ethyl-o-hydroxyanilino) 2 phenyl-S-pyrirnidinecarboxylic acid, a compound of structure XVII.

A mixture of 4-(o-ethylaminophenoxy)-2-phenyl-5- pyrimidinecarboxylic acid, ethyl ester (XVI) (7.0 g.), aqueous sodium hydroxide solution (50 ml.), and ethanol ml.) was refluxed for 1.5 hr., then acidified with dilute HCl to about pH 2. A precipitate thus deposited was collected on a filter and washed with ethanol, then with water to give 6.1 g. of product which melted at 150-174. Recrystallization from ethanol-water afforded a sample which melted at ISO-154, solidified and remelted at 190.

Anal.

Calcd. for C19H17N3O3I C, 68.05; H, 5.11; N, 12.53. Found: C, 67.50; H, 5.03; N, 12.39.

EXAMPLE 24 The following exemplifies the preparation of 4-(2- methoxyanilino) 2 phenyl-S-pyrimidinecarboxylic acid. ethyl ester, a compound of structure XIV.

A mixture of 4 chloro2-phenyl-S-pyrimidinecarboxylic acid, ethyl ester (5.0 g.), o-anisidine (12.0 g.), sodium carbonate (2.1 g.), and absolute ethanol (40 ml.) was refluxed for 2 hr. Chilling of the reaction mixture caused separation of a precipitate which was collected on a filter and washed with water to give 5.7 g. of product. Recrystallization from absolute ethanol alTorded an analytical sample, m.p. 145143.

Anal.

Calcd. for C H N O C, 68.75; H, 5.48; N, 12.03. Found: C, 68.69; H, 5.54; N, 11.98.

EXAMPLE 25 The following examplifies the preparation of 4- (N -ethylo-methoxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester, a compound of structure XIV.

A mixture of 4-chloro2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester (14 g.), N-ethyl-o-methoxyaniline which was obtained from o-methoxyacetanilide (27 g.) by Lithium aluminum hydride reduction, sodium bicarbonate (4.2 g.), and ethanol (30 ml.) was heated on a steam bath for 2 hr., then refluxed for 1 hr. Addition of a large amount of water caused separation of an oil. Purification of the oil by a fractional recrystallization from absolute ethanol afiorded 9.7 g. of product, mp 98-1005.

Anal.

Calcd for C22H23N303: C, H, N, 11.13- Found: C, 70.14; H, 6.34; N, 11.01.

' When tested in the foregoing pharmacological evaluation, the latter compound caused decreased motor activity at a dose of 127 MPK administered parenterally.

Following the procedure of Example 25, but substituting appropriate starting materials, products having the following substituents may be prepared.

(XVII) R3 10 R5 Ru Example 24 H C211 H H Example 25 A CzHs H CH3 CH3 H OH: CaH7 H C 11 C4Hu H C Hn H CH3 C211 Cl CH3 C2H5 F CH3 CH3 I C2H5 EXAMPLE 26 The following exemplifies the preparation of ll-ethyl- 2 phenylpyrimido[5,4 c] [1,5]ber.zoxazepin 5(11H)- one, a compound of structure XVIII.

' A mixture of 4- (N-ethyl-o-hydroxyanilino)-2-phenyl-5- pyrimidinecarboxylic acid (4.0 .g.) (XVII) and acetic anhydride ml.) was refluxed for 3 hr. Removal of the excess acetic anhydride under reduced pressure afforded an oil which solidified on standing to give 3.1 g. of product, mp 130-133. Recrystallization from absolute ethanol raised the mp. to 133-134".

Analy.

Calcd. for C H N O C, 71.91; H, 4.76; N, 13.24. Found: C, 71.90; H, 4.91; N, 13.62.

When tested in the foregoing pharmacological evaluation, the latter compound caused decreased motor activity at a dose of 400 MPK administered parenterally and decreased respiration at a dose of 400 MPK administered parenterally.

Following the procedure of Example 26, but substituting appropriate starting materials, products having the following substituents may be prepared.

(XVIII) The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized 1 9 that various modifications are possible within the scope of the invention claimed. I f

What is claimed is: 1. A compound having the formula 2. A compound as defined in Claim 1 which is 4-(o-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid.

3. A compound as defined in Claim 1 which is 4-(0-hydroxyanilino) -2-phenyl-5-pyrimidinecarboxy1ic acid, ethyl ester.

20 4. A compound as defined in Claim 1 which is 4-(5- chloro-Z-hydroxyanilino) 2 phenyl 5 pyrimidinecarboxylic acid, ethyl ester.

5. A compound as defined in Claim 1 which is 4-(N- ethyl 0 methoxyanilino) 2 phenyl 5 pyrimidinecarboxylic acid, ethyl ester.

6. A compound as defined in Claim 1 which is 4-(o-hydroxyanilino) 2 phenyl 5 pyrimidinecarboxylic acid, ethyl ester, acetate.

7. A compound as defined in Claim 1 which is 4-(N- ethyl 0 hydroxyanilino) 2 phenyl 5 pyrimidinecarboxylic acid.

8. A compound as defined in Claim 1 which is 4-(2-hydroxy 5 nitroanilino) 2 phenyl 5 pyrimidinecarbcxylic acid.

References Cited UNITED STATES PATENTS 3,254,086 5/1966 Juby 260-256.4 N 3,481,932 12/ 1969 Wagner 260256.4 N

JOSEPH A. NARCAVAGE, Primary Examiner .I. H. TURNIPSEED, Assistant Examiner U.S. CL. X.R. 

1. A COMPOUND HAVING THE FORMULA 